Hematin-Mediated Increases of Benzo(a)pyrene Monooxygenation in Maternal, Fetal and Placental Tissues of Inducible and Non-Inducible Mouse Strains

Abstract

The responses of hepatic and extrahepatic maternal and fetal tissues and placentas to the activating effects of hematin on cytochrome P-450-dependent monooxygenase (aryl hydrocarbon hydroxylase) activity were studied in two strains of mice. Tissues of a strain (C57BL/6J) that responds to the monooxygenase-inducing effects of 3-methyl- cholanthrene (3-MC) were compared with tissues of a non-responsive strain (DBA/2J) in order to determine whether hematin activation may play a role in the observed increases in extrahepatic monooxygenase activity following preexposure of pregnant animals to inducing agents. Maternal and fetal hepatic preparations from both strains of control mice exhibited decreased activity upon addition of hematin to reaction vessels. Monooxygenase activities in fetal hepatic preparations from both strains of 3-MC-pretreated mice also were decreased by hematin. Extrahepatic tissues of control C57BL/6J mice responded to the activating effects of hematin but the analogous tissues of 3-MC-pretreated mice of the same strain exhibited minimal or no significant response to hematin. The maternal brain tissue of DBA/2J mice exhibited a ninefold increase in monooxygenase activity upon addition of hematin in both the controls and 3-MC-pretreated mice. 3-MC-pretreatment of this strain resulted in abolition of hematin activation in fetal brain tissue but in the expression of statistically significant activation in placentas. Thus, no simple relationships between hematin activation and induction were evident, indicating that hematin activation is not responsible for the observation of increased enzymic activities in extrahepatic tissues after pretreatment with inducing agents.

Cytochrome P450 regulation: the interplay between its heme and apoprotein moieties in synthesis, assembly, repair, and disposal

“…An up to 70-fold stimulation of the metabolism of benzo[ a ]pyrene and similar substrates was observed after addition of heme to these homogenates, but similar heme addition to liver homogenates did not enhance the corresponding enzyme activities (Omiecinski et al ., 1978, 1980). A similar heme-dependent stimulation was also found with placental preparations from human and other species (Namkung et al ., 1983). Significant amounts of heme-reconstitutable CYP1A1 are also found in brain and kidney cytosol as detected both by immunoblotting analyses and EROD activity upon functional reconstitution with purified NADPH-cytochrome P450 reductase (Meyer et al, 2002).…”

Barbiturate and Ethanol Sleeping Times and Pharmacokinetics of Propranolol in Mice after Intravenous Administration of Haem Arginate

“…The hexobarbital sleeping time was significantly prolonged by a large single dose of haem arginate. This is in agreement with the finding that haematin impairs hepatic drug metabolism (Muller-Eberhard et al 1983;Namkung et al 1983). In the present study a single intravenous dose of haem arginate equivalent to 10 mg haem/kg did not prolong the hexobarbital sleeping time.…”

“…It has been demonstrated in tissue homogenates that haem may either stimulate or impair oxidative foreign substance metabolism (Namkung et al 1983;Ortiz de Montellano & Correia 1983). Haematin-mediated increases of mono-oxygenase activity have been demonstrated only in extrahepatic tissues of inducible mouse strain, but hepatic preparations from mice exhibited decreased activity upon addition of haematin to reaction vessels (Namkung et al 1983). The good clinical response to propranolol (Douer et nl.…”

Effects of repeated intravenous administration of haem arginate upon hepatic metabolism of foreign compounds in rats and dogs

“…In this study the lowest dose of haem arginate did not increase the oxidative metabolic capacity after one month of daily administration, which is to be expected because in addition to haem the apoprotein is also needed. Perhaps in extrahepatic tissues there is an excess of free apoproteins, which might explain why haematin could prove significant activation of monooxygenase activity in maternal or foetal brain tissues of mice (Namkung et al, 1983). With the higher doses of haem arginate, on the other hand, a reduction was seen in many parameters of foreign substance metabolism and this agrees with the findings of Namkung et al (1983) that the mono-oxygenase activities in maternal and foetal hepatic preparations of mice were decreased by haematin.…”